Magnetic ink tissue markings

ABSTRACT

The invention provides tissue markings (such as tattoos) comprising magnetic particles, e.g., magnetite, and methods for making and altering, e.g., removing them.

CLAIM OF PRIORITY

This application is a divisional of 10/913,114, filed on Aug. 6, 2004,and claims the benefit under 35 USC § 119(e) of U.S. Provisional PatentApplication Ser. No. 60/493,230, filed on Aug. 6, 2003. The entirecontents of the foregoing are incorporated by reference herein.

TECHNICAL FIELD

This invention relates to tissue markings, e.g., tattoos, and moreparticularly to magnetic particle tissue markings.

BACKGROUND

Tattooing is an ancient art, dating back as early as 12,000 BC (Grumet,Am. J. Orthopsychiatry, 53:482-492 (1983)), when ash was rubbed intoskin incisions. Puncture tattooing later became popular and is practicedeven today. Modern tattoo inks cover a wide pallet of colors and usedifferent tattoo “inks.” Today, about 1 in 5 young adults in the UnitedStates have been injected with these substances, by people with littleor no medical training.

The desire to remove tattoos is probably as old as their existence. Thefraction of tattooed people who will seek tattoo removal is unknown, butsubstantial. The earliest report of tattoo removal was by Aetius, aGreek physician who described salabrasion in 543 AD (Scutt, Br. J.Plast. Surg., 25(2):189-194 (1972)). Grossly destructive methods such asdermabrasion and argon or CO₂ laser vaporization are still used(Apfelberg et al., Br. J. Plast. Surg., 32:141-144 (1979); Apfelberg etal., Ann. Plast. Surg., 14:6-15 (1985); Bailin et al., J. Derm. Surg.Oncol., 6(12):997-1001 (1980); Reid and Muller, Plast. Recons. Surg.,65(6):717-728 (1980)), but they have a high risk of scarring. LeonGoldman first reported laser tattoo removal in 1965 and then in 1967using a Q-switched ruby laser (Goldman et al., J. Invest. Dermatol.,44:69-71 (1965)); Goldman et al., JAMA, 201(11):841-844 (1967)). Latercases reported by Reid et al. (Br. J. Plast. Surg., 36:455-459 (1983))revealed good results with a Q-switched ruby laser, particularly whenused on black and amateur tattoos. These results were further refinedbased on concepts of selective photothermolysis (Anderson and Parish,Science, 220:524-527 (1983)).

Because of the variety of tattoo ink colors, a variety of laserwavelengths are necessary to remove colored tattoos. High-energyQ-switched ruby (694 nm), alexandrite (755 nm), Nd:YAG (1064 nm) andfrequency-doubled Nd:YAG (532 nm), lasers are now used, which emitvisible and near-infrared light pulses ranging from about 10-100 nsduration (Levins et al., Lasers Surg. Med. Suppl., 3:63 (1991); Kilmerand Anderson, Dermatol. Surg. Oncol., 19:330-338 (1993); Kilmer et al.,Arch. Dermatol., 129:971-978 (1993); Fitzpatrick and Goldman, Arch.Dermatol., 130(12):1508-1514 (1994)).

Before laser treatment, tattoo ink particles are typically found withindermal fibroblasts and mast cells, predominantly in a perivascularlocation (Mann and Klingmuller, Arch. Dermatol. Res., 271:367-372(1981)). The mechanism by which Q-switched lasers remove tattoosinvolves selective rupture of these cells, breakdown of tattoo inkparticles, and ink removal by transepidermal elimination and/orlymphatic transport (Taylor et al., J. Invest. Dermatol., 97:131-136(1991); Ferguson et al., Br. J. Dermatol., 137:405-410 (1997)). The riskof scarring after Q-switched laser treatment is substantially lower thanafter excision, dermabrasion, or CO₂ laser vaporization. However, muchof the ink remains inside the body, either in regional lymph nodes or asa lightened, residual tattoo in the skin. The number of Q-switched lasertreatments required for complete tattoo “removal” depends on the type oftattoo ink, body location, and laser. Amateur tattoos made with carbon(ash, graphite, India ink) respond best, typically clearing in mostpatients after 4-6 treatments. Multicolored tattoos on the extremitiestend to respond poorly. Typically, less than half of these tattoos canbe cleared in less than ten treatments, regardless of the type ofQ-switched lasers used.

Tattoo inks are probably the least-regulated substances routinelyinjected into people in our society. The purity, pharmacology,biodistribution, and identity of most inks are unknown. None areapproved by the Food and Drug Administration (Anderson, N. Engl. J.Med., 326:207 (1992)). New bright-colored inks are being introduced atan unknown rate, and are often those most difficult to remove by lasertreatment. Although most tattoos appear to be well tolerated, there arereports of infection, photosensitivity, and acute and chronichypersensitivity reactions (Novy, Arch. Dermatol., 49:172-173 (1944);Bjornberg, Arch. Dermatol., 88:83-87 (1963); Loewenthal, Arch.Dermatol., 107:101-103 (1973); Goldstein, J. Dermatol. Surg. Oncol.,5:896-900 (1979)). Tattoo ink is permanently taken up in lymph nodes inaddition to the intended target organ, skin. The long-term health riskof tattooing is unknown. The present situation may eventually lead tosignificant problems.

In view of the history, popularity, limited safety data and limitedtreatment options for tattoos, safe, removable tattoo inks aredesirable.

SUMMARY

The present invention is based, in part, on the discovery that magnetite(Fe₃O₄) particles can be grossly and microscopically moved throughliving skin by external magnetic fields, and thus can be used to makesafe, removable tissue markings, e.g., tattoos. Thus, the inventionprovides novel “magnetic tattoo inks” comprising magnetic particles,e.g., magnetite particles, methods for making tissue markings using theinks, and methods and devices for removing tattoos made usingconventional black magnetite inks and/or the new magnetic inks describedherein. The magnetic particles can be of any size suitable for use intissue markings, but are typically in the micrometer or sub-micrometerrange, e.g., a range from about 0.1 to 5 micrometers, e.g., about 1 to 5micrometers, and should be uniform in size, e.g., vary by about, or lessthan, a factor of two, e.g., less than about 1 micrometer.

The magnetic particles can be black (e.g., the natural color of puremagnetite), or otherwise colored, e.g., coated or compounded with achromophore. In some embodiments, the particles can be coated, e.g.,with a clear or colored coating, e.g., a biocompatible, indispersible,and/or biologically inert coating to change the color of the particles,protect the particles, and/or render them more inert. In someembodiments, the coating can be or can include a chromophore, metaloxide, silica, glass, fluorocarbon resin, organic or inorganic polymer,wax, or any combination thereof. In some embodiments, the ink includesmagnetic particles of one color and non-magnetic particles of anothercolor, e.g., the magnetic particles are blue and the non-magneticparticles are yellow, or vice-versa. The colors blue and yellow are usedfor illustrative purposes only, and any colors can be used. In someembodiments, the mixture of particles of two colors produces magneticink of a third color; using the example of blue and yellow, the inkcould appear green.

In one aspect, the invention provides a sterile magnetic ink compositionincluding magnetic particles, e.g., magnetite (Fe₃O₄) particles, whereinthe magnetic particles are from 1.0 to 5 mm in diameter, and vary indiameter by less than a factor of about two. In some embodiments, theink also includes a carrier, e.g., ethanol; purified water; witch hazel;Listerine™; propylene glycol; glycerol; denatured alcohols; methanol;isopropyl alcohol; ethylene glycol; formaldehyde; glutaraldehyde;surfactants; and detergents.

In another aspect, the invention features a method of making a magneticink tissue marking, by implanting a magnetic ink composition describedherein into the tissue, e.g., skin. For example, the method can includeimplanting the magnetic tattoo ink composition to form a pattern in thetissue, such as a name, e.g., the name of a loved one, or a celebrity,or a sports team. In some embodiments, the method also includesimplanting a non-magnetic tattoo ink composition to form anotherpattern, to form a design that includes both the magnetic andnon-magnetic ink patterns. The magnetic tattoo ink composition andnon-magnetic tattoo ink composition can be the same or different colors;in some embodiments, the pattern formed by the implanted magnetic tattooink composition is a name, and the pattern formed by the implantednon-magnetic tattoo ink composition is a background for the name. Thesepatterns enable the removal of the named without disturbing thebackground.

In another aspect, the invention features a method of altering theappearance of a magnetic ink tissue marking including magnet-attractingparticles as described herein by applying a magnetic field to the tissuesufficient to move the particles to alter the appearance of the tissuemarking. In some embodiments, the method includes applying a lasertreatment, e.g., a Q-switched ruby laser treatment, before applying themagnetic field. In some embodiments, all or a part of the epidermis isremoved locally, or the dermo-epidermal junction is disrupted before themagnetic field is applied. In some embodiments, the magnetic field isapplied to the tissue for a length of time sufficient to cause themagnetic ink tissue marking to appear darker or to lighten or remove themagnetic ink from the tissue. In some embodiments, either theapplication of a magnetic field, the application of a Q-switched rubylaser treatment, or both, is repeated until the magnetic ink has beenaltered, e.g., darkened, lightened, or removed from the tissue. Thus,the method can be used to remove a particular color or pattern thatcomprises magnetic ink from the skin, e.g., removing a name; if the samelocation was tattooed with non-magnetic ink, the method can be modifiedso that patterns formed by the non-magnetic ink remain in the skin,e.g., by modifying the intensity or wavelength of the laser treatments.

In another aspect, the invention features a device for removing magneticink skin tattoos, the device including means for producing a highproduct of the magnetic field strength and magnetic field gradientwithin the skin, e.g., at least one magnet, e.g., a permanent magnet oran electromagnet, e.g., a superconducting electromagnet or a solenoidcoil and a housing configured to enable the device to be contacted tothe skin in the location of a tattoo. In some embodiments, the deviceincludes a controller that can be used to vary the magnetic fieldspatially or temporally, or both. In some embodiments, the deviceincludes a laser, e.g., a Q-switched ruby laser, such as a laser used ina conventional laser treatment device.

In a further aspect, the invention provides methods for attachingmagnetic objects to a portion of skin, by implanting a magnetic tattooink composition as described herein in a manner sufficient to create amagnetic area on the skin, and attaching a magnetic object to the skin.In some embodiments, the magnetic tattoo ink composition issubstantially the same color as the skin, and so is invisible to thenaked eye.

As used herein, an “indispersible” substance (such as a coating materialor an individual particle) does not disintegrate, dissolve, or becomemetabolized in tissue. An “inert” or “biologically inert” substance ormaterial (such as the coating material of a particle) generally createsno significant biochemical, allergic, or immune response after thenormal healing period when implanted into living tissue.

The invention provides several advantages. For example, magnetic inktissue markings can be altered, e.g., changed, updated, or removed, bythe application of a magnetic field, or by the application of atreatment to free the particles from engulfing cells, e.g., lasertreatment, followed by application of a magnetic field.

Magnetite (Fe₃O₄) is a non-toxic, insoluble, stable, jet-black compound,which can be used to make tissue markings that can be altered by bothlasers and external magnetic fields. Thus, an individual can now chooseto have a tattoo that can be more easily removed or altered than tattoosmade using conventional tattoo inks and removed using conventionaltechniques. The removal methods of the invention are applicable to,e.g., can be used to remove, both the magnetic inks described herein,and to tattoos made with conventional inks that have magnetic particles.

As used herein, “magnetic” means capable of being attracted by a magnet,or capable of being magnetized. As used herein, a “magnetic particle”refers to a particle that is a magnet, or is capable of being attractedby a magnet, e.g., capable of being magnetized, e.g., a particlecomprising in whole or in part Fe₃O₄.

As used herein, a “permanent tissue marking” or “tissue marking” is anymark created by the introduction of particles into tissue, typicallyliving tissue, with the intention of permanent or long-term endurance.Markings can be any color and can be detectable, for example, by thenaked eye, when exposed to electromagnetic radiation in one or moreregions of the spectrum, for example, the visible or near-infraredregions. A permanent marking is generally a marking that remains visibleor otherwise detectable (e.g., under the proper illumination) until itis exposed to a specific energy.

As used herein, a “tattoo” is a type of tissue marking wherein thetissue is usually skin. “Standard tattoos” and the inks and pigmentsused to create them do not typically have strong magnetic properties.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. All publications, patentapplications, patents, and other references mentioned herein areincorporated by reference in their entirety. In case of conflict, thepresent specification, including definitions, will control. In addition,the materials, methods, and examples included herein are illustrativeonly and not intended to be limiting; methods and materials similar orequivalent to those described herein can also be used in the practice oftesting of the methods and compositions described herein.

Other features and advantages of the invention will be apparent from thefollowing detailed description, and from the claims.

DESCRIPTION OF DRAWINGS

FIGS. 1A-1D are photographs showing the appearance of magnetite tattooson an albino rat. 1A, untreated mature tattoo. 1B, immediately afterQ-switched ruby laser (QSRL) treatment, showing immediate whitening. 1C,magnet affixed to a magnetite tattoo, held in place by magneticattraction. 1D, magnet sutured in place after laser treatment, for3-week application.

FIG. 2 is a photomicrograph showing the histological appearance of a 4month old magnetite ink tattoo. There is a predominance of ink (arrows)in the middle and deep reticular dermis, without a streaking pattern.Scale bar 100 um, 4x, eosin stained. MT, magnetite tattoo ink. E,epidermis.

FIGS. 3A-3D are photomicrographs showing the histological appearance oftattoos treated with QSRL and magnets. 3A, mature magnetite ink tattootreated with magnets alone. 3B, one hour after QSRL treatment followedby magnet application, showing increased ink in the papillary dermisunder an intact epidermis. 3C, one hour post QSRL treatment followed bymagnet application without an intact epidermis. 3D, three weeks postQSRL treatment, with magnet application for three weeks. Ink issignificantly retained in the papillary dermis close to thedermo-epidermal junction (DEJ), compared with controls. Eosin stain,scale bar 100 um, 4x. E, epidermis; St, streaking.

FIGS. 4A-4B are photomicrographs showing the histological appearance oftattoos treated with QSRL alone. 4A, one hour post QSRL treatment, inkparticles are dispersed throughout the reticular dermis and there is nostreaking pattern. 4B, three weeks post QSRL treatment, there issignificant clearing of ink from the papillary and reticular dermis.Eosin stain, scale bar 100 μm, 4x. E, epidermis.

FIG. 5 is a bar graph illustrating the amount of tattoo ink in thepapillary dermis. Tattoos treated with QSRL and magnets hadsignificantly greater ink in the papillary dermis (*).

FIG. 6 is a bar graph illustrating the degree of vertical streakingpattern. Application of magnets after QSRL causes streaking pattern inthe dermis, apparently along magnetic field lines. Key for FIGS. 5 & 6:A, Tattoos alone; B, one hour post QSRL alone; C, one hour post QSRL andmagnet; D, 3 weeks post QSRL and magnet; E, 3 weeks post QSRL alone; F,one hour post magnet alone.

FIGS. 7A, 7B, and 8 are line drawings showing cut-away, not to scaleviews of a simple hand-held electromagnet device, before application ofa magnetic field (FIG. 7A) and after (FIG. 8); FIG. 7B shows theinclusion of a laser.

DETAILED DESCRIPTION

It has been demonstrated that tissue markings (e.g., tattoos) comprisingmicrometer-sized magnetic particles (e.g., magnetite) can be grossly andmicroscopically manipulated in vivo by external magnetic fields.Magnetic particles, e.g., magnetite particles, can be successfully usedto create tissue markings, e.g., tattoos, which can be altered, e.g.,changed, updated, or removed, by the application of magnetic fields.

Magnetite is a biodegradable, biocompatible, non-toxic molecule that hasbeen used as an MRI contrast agent (Weissleder et al., Am. J.Roentgenol., 152:167-173 (1989). Other magnetic particles, such as redand black iron oxides (Fe₂O₃, FeO, and Fe₃O₄) can also be used in thenew methods. Unlike other tattoo inks, iron oxides have not beenreported to cause hypersensitivity reactions. The most common tattoo inkcolor is black, and, as demonstrated herein, magnetite makes blacktattoos nicely. A pure, sterile, optimized suspension of magnetite canbe produced as an alternative to other black inks, which can includecarbon and FeO. Magnetic inks can also be produced in colors other thanblack, for example by coating magnetic particles, e.g., magnetiteparticles, with a chromophoric substance.

Magnetic Ink for Tissue Markings

In some embodiments, the invention includes a composition suitable foruse in tissue marking, e.g., a “magnetic ink,” including magneticparticles, e.g., magnetite particles. The particles can be of any sizesuitable for use in tissue markings, but are typically in the micrometeror sub-micrometer range, e.g., about 0.1 to 5.0 micrometers, e.g., about1 to 5 micrometers. Typically, the particles will comprise magnetite(Fe₃O₄), but a number of components can equally be used, e.g., metals(including the magnetic elements, such as iron, nickel, cobalt,chromium, or manganese) or magnetic organic polymers (see, e.g., Rajcaet al., Science, 294:1503-1505 (2001)). The particles can be made of100% metal oxide (e.g., magnetite), or can be composites including othercomponents, e.g., polymers, e.g., polymer-bonded magnets, and/orpolymers comprising chromophores. In some embodiments, the ink comprisespolymer particles filled with magnetic, e.g., magnetite, nanoparticles.In some embodiments, the particles are encapsulated with an inert,colored coating, e.g., a polymer comprising a chromophore to formmicrospheres.

Unlike conventional magnetite-containing black tattoo inks currently inuse, which comprise magnetite particles that can vary dramatically insize (e.g., by about an order of magnitude), typically, the magneticparticles described herein will be of a uniform size, e.g., vary indiameter by less than a factor of two, e.g., 1-2 micrometers. In someembodiments, the particles are, for example, about 1-2 micrometers,about 2-4 micrometers. In some embodiments, the diameter of theparticles varies by less than about 1 micrometer, e.g., about 0.75micrometers, about 0.5 micrometers, about 0.25 micrometers, or about 0.1micrometers.

In some embodiments, the particles are magnetized, e.g., capable ofattracting iron (e.g., project their own magnetic field), and producinga magnetic field outside themselves, either naturally or by induction.In some embodiments, a magnetic field can be induced in the particles,e.g., during manufacture and/or after implantation into the tissue, byexposing the particles to a strong magnetic field, e.g., anelectromagnet. In some embodiments, the magnetic field created is fromabout 200 to about 25,000 or more gauss, e.g., 500, 800, 1000, 2500, or12,500 gauss (10,000 gauss=1 Tesla). In some embodiments, the magneticparticles retain the ability to project a magnetic field, i.e., theybecome permanent magnets. In some embodiments, the particles may losethe ability to produce a magnetic field over time, and a field can bere-induced by re-application of a strong magnetic field.

The magnetic particles can be fabricated using methods known in the art,including, but not limited to, mechanical milling, supercriticalCO₂-based precipitation of magnetite/polymer microparticles, or micellesynthesis. After fabrication, the particles can be sorted for size andquality, e.g., by centrifugation or filtration. A number of magneticparticles are commercially available, e.g., from Ademtech, 33600 Pessac,France; Bangs Laboratories Inc., Fishers, Ind., U.S.A.; Pea Ridge IronOre Co., Sullivan, Mo.; Quantum Magnetics, Division of ClementeAssociates Inc., Madison, Conn., U.S.A.; and many others. A list ofmanufacturers can be found on the world wide web atmagneticmicrosphere.com/supply.htm. The particles can be sterilizedusing methods known in the art, e.g., heat, chemical, or radiationsterilization.

The magnetic particles can be black or colored, e.g., coated with orsynthesized with a chromophore, e.g., any chromophore typically used intissue marking applications, e.g., colored or white tattoo ink, or, forexample, any colored substance approved by the United States Food andDrug Administration for use in humans, e.g., rifampin, β-carotene,tetracycline, indocyanine green, Evan's blue, methylene blue, FD&C BlueNo. 1 (Brilliant Blue FCF), FD&C Green No. 3 (Fast Green FCF), FD&C RedNo. 3 (Erythrosine), FD&C Red No. 40, FD&C Yellow No. 5 (Tartrazine), orFD&C Yellow No. 6 (Sunset Yellow FCF).

In some embodiments, the magnetic particles can be coated, e.g., with aclear coating, e.g., a substantially visibly transparent, biocompatible,indispersible, and/or biologically inert coating to protect theparticles or render them more inert. Substances fitting these criteriathat are capable of encapsulating particles useful in the newcompositions include waxes with a melting point substantially above bodytemperature, for example, natural waxes, synthetic waxes, and waxmixtures, specifically Polywax® and carnauba wax; plastics and organicpolymers, for example, parylenes, polyamide, polyvinyl acetate, ureaformaldehyde, melamine formaldehyde, ethylene acrylate, cyanoacrylates,butadiene-styrene, and specifically biocompatible materials such asEpo-Tek® 301 and/or 301-2, manufactured by Epoxy Technology, Billerica,Mass.; metal oxides, for example, TiO₂, silica (SiO₂), BIOGLASS®, KG-3and BG-7 manufactured by Schott, Inc., Germany, and other glasses (SiO₂plus any one or more of the following: Na₂O, CuO, B₂O₃, MgO, Al₂O₃,P₂O₅, and others); inorganic fluorine-containing compounds such as MgF₂;and fluorocarbons such as TEFLON®. In some embodiments, the coating is anoble metal, e.g., Ag, Au, or Pt. The material for coating should notinterfere with the magnetic properties of the particle.

In some embodiments, the magnetic particles are coated first with achromophore, and then with a clear outer coating.

In some embodiments, the particles are provided dry, e.g., substantiallyfree of any liquid carrier. In some embodiments, the particles areprovided in a concentrated liquid form, e.g., to be diluted before useor application, or in a concentration suitable for use directly. In someembodiments, the particles can be provided in, or diluted into, acarrier, e.g., a carrier known in the art, including but not limited toethyl alcohol (ethanol); purified water; witch hazel; Listerine™;propylene glycol; glycerin (glycerol); denatured alcohols; otheralcohols (methyl alcohol or methanol and isopropyl alcohol or rubbingalcohol are commonly used); ethylene glycol; aldehydes, such asformaldehyde and glutaraldehyde; or various surfactants or detergents.The carrier can be clear, e.g., not imparting any color to the skin, orcolored. In some embodiments, the particles are mixed into a standard,non-magnetic tattoo ink, to provide a colored and magnetic tattoo.

A number of standard tattoo inks are known in the art and arecommercially available. In some embodiments, powdered standard ink canbe dissolved into the magnetic ink of the invention. In otherembodiments, powdered standard ink and dry particles of the inventionare dissolved together in a suitable carrier. In some embodiments, themagnetic inks of the invention will be provided in one or more colors,e.g., colors in addition to or instead of black, and a magnetic, coloredtissue marking can be created using only magnetic inks. In someembodiments, the magnetic ink comprises magnetic particles of one colorand non-magnetic particles of another color. When such an ink is used tomake a tissue marking, the marking has a color resulting from themixture of the two (e.g., blue magnetic particles plus yellownon-magnetic particles make green ink). At a later date, the magneticparticles can be removed, e.g., by a methods described herein, leavingonly the non-magnetic particles, thus changing the color of the tissuemarking.

Methods of Making Tissue Markings

The magnetic inks can be used to make any type of tissue marking,including artistic tattoos (“body art”), or for identification. Someexamples of markings to fill identification needs include markings toassist tracking bodily sites of medical interest in external andsuperficial internal tissue, for example, marking a radiation therapyfield on the skin, or marking a colon polyp in the intestine which cansubsequently be monitored endoscopically; identification markings forhumans, for example, emergency information regarding an individual'smedical history, “dog-tags” on military personnel, and identificationmarkings on newborn babies to ensure no hospital mix-ups; andidentification markings for animals (such as wild animals, livestock,sport/show animals, and pets), for example, information markings for thereturn of lost pets.

The magnetic inks of the present application can be applied usingconventional tattooing methods and equipment, e.g., standard oscillatingspring point machines such as the commercially available Technical,Paolini, Joe Kaplan, Black Lotus, or Mao Tattoo Machine. The magneticinks can be applied using standard or specialized tattoo needles, suchas are described in U.S. Pat. No. 6,345,553. The magnetic inks can beapplied alone or with other inks, e.g., standard colored tattoo inks,e.g., mixed together or applied separately.

The compositions can be tested by injection into the dermis of ananimal, e.g., a guinea pig, a Yucatan micropig, a fuzzy rat, or ahairless albino rat, at different amounts of delivered material, e.g.,with a standard oscillating tattooing machine. Healing of the skin canbe allowed, e.g., for about one month, and the quality and darkness ofthe tattoos can be observed and measured, e.g., using a collimated lightsource and digital camera apparatus. Skin reactions to the tattoo canalso be observed, e.g., for signs of persistent inflammation,elimination and stability of the tattoos, e.g., over an extended periodof time, e.g., weeks, months, or more. The amount of material needed forproviding a given line or darkness can also be measured.

The magnetic ink compositions described herein can be used to maketissue markings that can be altered, e.g., removed, by the applicationof a magnetic field, e.g., an external magnetic field. The tissuemarkings can include markings made using conventional inks and/or inksincluding both magnetic and non-magnetic particles, thus, theapplication of the magnetic removal methods of the present inventionwill alter the magnetic portion, but can leave the non-magnetic portionuntouched. As one example, non-magnetic inks can be used to make abackground design, and magnetic inks can be used to inscribe the name ofa person, e.g., a significant other. If the relationship later ends, theperson's name can be removed, leaving the background design.

Tattoo Alteration Methods

The invention also includes methods for the alteration, e.g., removal,of tissue markings comprising, e.g., the magnetic inks described herein,or conventional black ink comprising magnetite particles.

In some embodiments, magnetic fields alone can be used to alter orextract magnetic ink tattoos, i.e., without the need for laser treatmentto free particles from within dermal cells. As described in the Examplesbelow, 1.4 μm magnetite particles, implanted as a tattoo in rat skin,can be manipulated using external magnetic fields (see also, Huzaira andAnderson, Lasers Surg Med., 31:121-128 (2002)). Although application ofmagnets for an hour to mature magnetite skin tattoos in rats, withoutlaser treatment, did not cause significant ink particle movement byhistological analysis (p=0.133), there was re-arrangement of themagnetite, as evidenced by streaking along magnetic field lines (seeExample 1 and FIG. 3A). Tattoo ink is typically contained in cells,mainly macrophages, fibroblasts, and mast cells. Although the magneticforces produced for 1 hour under the conditions described in Example 1(below) were apparently not sufficient to overcome cell-matrix adhesionin the dermis, long-term application of magnets to tattoos, and/or morepowerful magnetic fields, can “drag” cells, loaded with magneticparticles, through the dermis, thus removing the tattoo. The forceexerted on a magnetite particle within the dermis by a magnetic field isproportional to the product of the magnetic field strength and themagnetic field gradient.

In some embodiments, a treatment is applied in combination with magneticfield use, e.g., before application of a magnetic field for extractionof magnetite particles, which “frees” the particles from cells in thedermis, e.g., a treatment that can be used to selectively destroy thecells enclosing the particles, e.g., a laser treatment, such as aQ-switched laser treatment, which heats the particles sufficiently to“boil” water molecules surrounding the particles, thus rupturing thecells in which the particles are imprisoned. Alternatively or inaddition, one or more powerful pulses from an electromagnet can be usedto “free” the particles, and the same or another magnetic device canthen be used to attract the particles for removal from the skin, afterwhich the ink particles can be more easily dragged through the dermistoward a magnet at the skin surface. In the dermis, the particles lineup along what appear to be magnetic field lines. Some particles can bephysically extracted within an hour, if the epidermis is not intact. Asone theory, not meant to be binding, the magnetite particles traversethe dermis until they reach an intact dermo-epidermal junction, whichacts as a barrier. Magnets applied for several weeks after lasertreatment cause a darker tattoo, probably by bringing more of the inkinto the upper dermis. Thus, laser treatment followed by selectivelong-term application of magnets, or long-term application of magnetsalone, can be used to darken or remove selected areas or all of atattoo. In some embodiments, the method includes repeating the lasertreatment and/or application of magnetic field until the magnetic inkhas reached a desired lightness (e.g., been removed), or darkness (e.g.,a desired amount of the magnetic ink has been brought to the surface ofthe tissue).

The fact that micrometer-sized particles can be easily forced totraverse the dermis is remarkable and unexpected. The broad implicationfor tattoo removal is that a Q-switched laser treatment followed by anyadjunctive treatment which enhances and/or forces particle motion,provides an effective method to remove tattoos. While magnetic fieldsare a convenient and effective model system, this is not the only meansfor forcing particle motion. For example, more mechanical means, such astissue massage using gross vibratory motion or alternatively ultrasonicvibratory motion applied after laser treatment and/or a directed flow ofextracellular fluid to wash particles through the dermis, can beemployed.

The present results indicate that the epidermis or dermo-epidermaljunction may block extraction of tattoo ink. Therefore, intentionalremoval of the epidermis followed by forced-ink-extraction, e.g., usinga magnet, will also be effective. For example, the dermo-epidermaljunction can be disrupted using a CO₂ laser (Ort et al. (Lasers Surg.Med., 26 (suppl 12):23 (2000)).

An alternative to ink extraction would be to force ink in the oppositedirection—to the bottom of the dermis and “out of sight.” Asdemonstrated herein, long-term application of a magnet to intact skinafter laser treatment darkened the tattoo by moving ink into the upperdermis. By placing the magnet under the skin, e.g., surgicallyimplanted, the magnet would attract the magnetic ink deeper into thetissue and the tattoo would lighten. Alternatively, the particles can beprovided with a specific charge, and a device to drive the particlesdeeper into the skin would have an opposite charge.

Vertical streaking of magnetic tattoos in the dermis was uniquelyassociated with magnet application. The streaking pattern is consistentwith magnetic field lines, which can be seen in any setting whereparamagnetic or superparamagnetic particles are free to move in responseto a permanent magnet. The particles clump together and form an orientedstreak because of particle-particle interactions. Within each particle,magnetic polarization occurs in response to the external magnetic field,such that each particle becomes a small magnet. Head-to-tail alignmentof particles along the external magnetic field then occurs. Thus, astationary magnetic field can be used to create lines in the tissuemarking along the field.

Alternatively, a time-varying magnetic field can be used, e.g., to bringthe magnetic particles to the surface in a more uniform manner, or toextract the magnetic particles from the dermis. Alignment and clumpingof magnetite tattoo particles within the skin of rats occurs along thefield lines of a permanent magnet applied to a magnetite skin tattoo, asdescribed. This alignment is due to interactions between adjacentparticles' magnetic fields, and the clumping tends to limit extractionof individual particles. An advantage of a time-varying magnetic field,e.g., a field which is modulated such that its polarity switches, isthat particle clumps will tend to dissipate more, as compared with theparticle clumps in a static magnetic field. As one theory, not meant tobe binding, some particles may enter cul-de-sacs created byextracellular matrix proteins and various skin structures.

A spatially-varying magnetic field would minimize this problem. Aspatially-varying magnetic field is a field in which the spatialcontours, locations, and/or shape of the magnetic field lines changeover time. This can be accomplished by physically moving a permanentmagnet or magnets over the skin containing a magnetite tattoo, tospatially vary the magnetic field within the skin tissue. Spatialvariation can also be achieved by activation of different coils within amulti-coil electromagnet, which may or may not be physically moved overthe skin tissue. Thus, a time- and spatially-varying magnetic field canbe used, e.g., to more completely extract the magnetic particles.

Magnetic tattoo manipulation can be optimized, e.g., by varying thechoice of magnets, magnetic field strength, magnetic field gradient,time of application, magnetic particle size and strength, and otherfactors. For example, permanent magnets having a field force of at leastabout 0.5 Tesla, e.g., about 1 Tesla, about 1.5 Tesla, about 2 Tesla, ormore, can be used. The magnets can be applied for varying periods oftime, e.g., 1 hour, 1 day, 1 week, several weeks, a month, or severalmonths. The motive force exerted by a magnetic field on a paramagneticmaterial (such as Fe₃O₄) is approximately proportional to the magneticmoment of the particle, and to the product of the magnetic fieldstrength and the local magnetic field gradient. Although there areintrinsic limitations to the field strength and gradient of permanentmagnets, electromagnets can be constructed specifically for tattoomanipulation, thus offering the options of higher field strength,pulsing and/or switching of the field polarity. Such electromagnets areknown in the art and can be constructed by one of ordinary skill in theart, or can be purchased from a commercial or custom supplier. Forexample, solenoid coils are commercially available electromagnets thatspan a range of sizes and strengths. For much more powerful fields,superconducting (cold) electromagnets can also be used. These are mostcommonly used in medicine for magnetic resonance imaging (MRI), whichmust produce a stable magnetic field across the entire human body. Muchsmaller superconducting electromagnets producing field strengths up toapproximately 20 Tesla could be used for magnetic tattoo extraction.

Devices for Altering Magnetic Tattoos

As noted above, the force exerted on a magnetic particle within thedermis by a magnetic field is proportional to the product of themagnetic field strength and the magnetic field gradient. Thus, theinvention also includes devices, useful in practicing the methodsdescribed herein, which are capable of creating a high product of themagnetic field strength and the magnetic field gradient. Suitabledevices can be used to create an external magnetic field that can beused to alter, e.g., remove magnetic ink tissue markings, e.g.,magnetite tattoos. Such devices can comprise external permanent magnetsor electromagnets suitable for use in the methods described herein. Suchdevices can include controlling devices capable of producing atime-varying, spatially-varying, and/or time- and spatially-varyingmagnetic fields.

FIGS. 7A and B are schematic diagrams showing a cut-away, not to scaleview of one embodiment of the new devices, comprising a simple hand-heldelectromagnet device 10, arranged within housing 11, configuredspecifically to produce a high product of the field x field gradientnear a pointed or tapered soft-iron core 12, which is placed in or nearcontact with the skin 20. DC or alternating or pulsed current isgenerated by a power supply 18, and transmitted via flexible cable 14 toelectromagnetic coil 13 to produce the magnetic field 16. The powersupply 18 can be internal to the housing, e.g., a battery, or external,e.g., the device can be plugged into an outlet. If alternating or pulsedcurrent is supplied, the magnetic field will be time-variant. The device10 is intended to be held in or near contact with skin, and passed alongthe skin surface to produce a spatially-varying magnetic field. Otherdetails of the device are known in the art, e.g., supporting structures,user interface, power supply controls, etc., all of which are well knownin the art of making electrically-powered medical devices. The desiredpeak magnetic field strengths range up to about 20 Tesla, and are moretypically around 0.5-5 Tesla, at the “business” tip of the device.

During treatment, magnetic particles 24 in the dermis 21 are attractedto and migrate toward the device's tip, entering the upper dermis,epidermis 22, and/or extracted from the skin 20. In FIG. 8, theparticles 24 have migrated to the upper dermis 21 and epidermis 22. Thedermo-epidermal junction 23 is at least a partial barrier for migrationof particles 24 into epidermis 22. Once in the epidermis 22, theparticles 24 will be naturally shed over the period of about one month,because the epidermis 22 is constantly growing outward and shedding.

In some embodiments, it may therefore be desirable to remove theepidermis, or the epidermis and the upper dermis, either before or afterapplication of the magnet, e.g., using dermabrasion or laserresurfacing. These procedures for removing epidermis and upper dermis donot cause permanent scars when properly performed to a depth of about0.1-0.3 mm (this limits the depth to the epidermis and upper, so-calledpapillary, dermis). Alternatively, suction can be applied to the skin tocreate a suction blister at the dermo-epidermal junction (a separationbetween the dermis and epidermis, which can be induced by methods knownin the art, e.g., devices such as those described in Kiistala, J.Invest. Dermatol., 50(2):129-37 (1968), with or without the applicationof heat), either before or after the application of a magnetic field asdescribed herein. Once the particles are brought to the junction, theparticles will end up in the blister fluid filling the suction blister,and can be quickly removed, e.g., by removing the fluid via a syringe,and the dermis can then be allowed to lay back down and heal.

As shown in FIG. 7B, a variation of device 10 adds a laser 31, such as aQSRL, to the device, that applies laser light 33 (e.g., a lasertreatment) to a location on the skin and thereafter or simultaneouslyapplies the magnetic field 16 to the same location. In some embodiments,the laser 31 comprises a fiber optic cable 32 that delivers the laserlight 33 to the location. In some embodiments, this device can include aprogrammable controller that allows the user to set the strength,intensity, and/or duration of the laser and/or magnetic field applied tothe skin, e.g., to vary the magnetic field temporally and/or spatially,or to vary the wavelength of the laser treatment.

Temporary Magnetic Body Art

In another aspect, the invention provides methods of decorating thebody, e.g., any part of the body. Once a magnetic ink tissue marking hasbeen created, magnetic decorative items can be attached. For example, anarea of the body, e.g., the arm, earlobe, forehead, navel, or ankle, istattooed using the magnetic ink described herein. Once the tattoo hashealed, decorative items attached to small, strong magnets (e.g., about0.5 Tesla, 1 Tesla, 1.5 Tesla, 2 Tesla, or more) can be temporarilyadhered to the skin.

In some embodiments, the decorative item is an item of jewelry. In someembodiments, the decorative item is made to look like, e.g., an animal,an insect, a flower, or a leaf. In some embodiments, the decorative itemis made to look like an unnatural body part, e.g., an extra eye or ahorn. In some embodiments, the magnetic ink comprises particles coatedwith a chromophore so as to make the tattoo practically invisible to thenaked eye, so that it is not generally visible, but provides a locationto hold magnetic items. Thus, the invention also includes methods ofcreating an attachment site for magnetic items, by implanting asufficient amount of magnetic ink, e.g., the magnetic ink describedherein, subdermally to create an area of “magnetic skin,” which has asufficient attraction to or for a magnetic decorative item to hold thedecorative item in place, but allows the decorative item to be removedpainlessly. The invention also includes decorative magnetic itemssuitable for use as temporary magnetic body decoration or body art.

EXAMPLES

The invention is further described in the following examples, which donot limit the scope of the invention described in the claims.

Example 1 Magnetite Tissue Markings

Described herein is a small animal study of a novel magnetic “ink” andremoval methods. Magnetite (Fe₃O₄, Pea Ridge Iron Ore Company, Inc.;item code M-25; Sullivan, Mo.) particles, 1.4 Mm in diameter were mixedin glycerin (20% w/w), which provides sufficient viscosity for asuspension. The particle size was chosen to be within the 0.5 to 4 μmrange typical for skin tattoos (Taylor et al., J. Invest. Dermatol.,97:131-136 (1991)). The suspension was used to make magnetite tattoos. Astandard oscillating tattoo machine with needle array for commercialtattooing was used (Spaulding and Rogers, Albany, N.Y.), set to apuncture depth of approximately 1 mm. Fifteen hairless, albino rats wereused for the study. The animals were anesthetized by a combination ofketamine, 45-75 mg/kg and xylazine 10-20 mg/kg, given intramuscularly. Atotal of 72 tattoos, each 1×3 cm, were made on the backs of the rats,and allowed to mature for 4 months before any treatment was done.

Photographic Analysis: A Nikon Digital camera (Nikon Digital, ChannelRGB, E950, 6V, 0.8 A NTSC, Japan) was used to take pictures before lasertreatment, one hour after treatment, 1 week post treatment, 2 weeks posttreatment and 3 weeks post treatment. As a measure of relativelightening or darkening, a pixel histogram analysis (Corel Photo Paint8, Channel RGB, Windows NT) was performed from the digital images.Relative lightening or darkening was measured by the mean pixel value inphotographs within the region of interest (ROI) defined by the tattooedarea of skin. Pixel values ranged from 0-255 because of the standard8-bit digitization, with 0 being the maximum dark value and 255 beingthe maximum bright value. Pixel values were used for statisticalanalysis (see below).

Histologic analysis: 6 mm punch biopsies were obtained from treated andcontrol sites at the following time points: before treatment; one hourpost treatment; one week post treatment; 2 weeks post treatment; and 3weeks post treatment. The biopsy wounds were closed with 4-0 silksutures, which were removed after one week. Biopsy samples wereimmediately fixed in 10% formalin, then processed routinely and embeddedin paraffin. Vertical sections were obtained and stained lightly witheosin, in order to easily see the magnetite tattoo ink particles.Standard hematoxylin and eosin staining of sections was also performed.The sections were blindly analyzed by three histopathologists for thefollowing features: amount of ink in the papillary dermis on a scale of0-5, with 5 being a maximum; and the presence of alignment and verticalstreaking patterns of magnetite particles on a scale of 0-5, with 0being no streaking and 5 being the most obvious streaking pattern.

Statistical analysis: Measures included the pixel values from eachtattoo image, ratings of ink in the papillary dermis, and ratings ofvertical streaking pattern in the papillary dermis. The mean, standarddeviation and median of pixel values for each treatment condition werecalculated. To compare the non-parametric data, Kruskal-Wallis testswere used. After Kruskal-Wallis tests, a post-hoc Mann-Whitney test wasperformed, and the global p value was corrected by Bonferroni test(p<0.05).

Results

The magnetite made dark black or blue-black skin tattoos, which healedeasily and were stable. No evidence of inflammation or scarring wasnoted at a four month follow-up after making the magnetite tattoos. Theaverage brightness, as determined by pixel value of untreated tattoos,was 97 out of 255 (FIG. 1A). Histological analysis showed inkpredominantly in the mid to deep reticular dermis, where the inkparticles were in small clusters without any particular alignment (FIG.2). The results of the statistical analysis of the amount of tattoo inkin the papillary dermis are shown in FIG. 5; results of statisticalanalysis of vertical alignment and streaking are shown in FIG. 6.

Example 2 Removal of Magnetite Tissue Markings

A Q-switched ruby laser (QSRL) and permanent magnets were investigatedas agents for potentially clearing the tattoos, alone and incombination.

The tattoos were divided into six groups. Twelve tattoos per group werestudied grossly and histologically after the following manipulations:tattoos alone (no treatment, control; Group A in FIGS. 5 and 6); 1 hourpost QSRL alone (Group B); 1 hour post QSRL and magnet (Group C);3-weeks post QSRL alone (Group E); 3-weeks post QSRL and magnet appliedfor 3 weeks (Group D); short-term (1 hour) application of magnet alone(Group F). The QSRL (Spectrum RD1100; Palomar Medical Products Inc.,Burlington Mass.) had a nominal pulse duration of 30 nsec and wavelengthof 694 nm. Treatment exposure fluence was 4.5 J/cm² with a 6.5 mm spotsize, and partial overlapping of the pulses to avoid skipping areas oftreatment. Permanent magnets of 1.4 Tesla (Neodymium alloy, a gift fromJ. Dallarosa, Coherent Inc., Santa Clara, Calif.) 600 mg and 6 mmdiameter were used, applied to the skin surface overlying the tattoosalone and in combination with prior laser treatment. These are among themost powerful small permanent magnets which are readily available. Athin layer of tegaderm tape was applied between the magnet and thetattooed skin, to avoid direct contact of the skin with the magnet.Short-term application of magnets (one hour) was achieved by directlyplacing the magnet on the skin with tegaderm tape in between, while theanimal was still anesthetized. Attractive force between the magnets andtattooed skin was easily perceived, and were sufficient to “stick” themagnets to the skin surface (FIG. 1C).

Long-term application of magnets (3 weeks) was achieved by adhering themagnet to a thin plastic disc 1 cm in diameter, and suturing the disc tothe skin surrounding the magnetite tattoo (FIG. 1D). Wound care afterplacing tattoos and after laser treatment consisted of cleansing anddaily application of bacitracin ointment for 7 days, after which anyepidermal injury had healed.

Results: Short Term Application of Magnets Alone

Magnets applied for one hour did not significantly affect tattoobrightness (p=0.285) compared to untreated tattoos. Biopsies taken onehour after the application of magnets on mature tattoos without lasertreatment, revealed no significant change in particle distribution(p=0.133) compared with untreated stable tattoos. FIG. 3A shows a maturemagnetite ink tattoo treated with magnets alone. There is no significantdifference in the amount and distribution of ink compared to FIG. 2,however some streaking characteristic of magnet application is seen(arrows).

In 4 out of 12 biopsy samples, magnets produced a minor degree ofvertical streaking pattern, which was not statistically different fromuntreated tattoos (p=0.071; see FIG. 6).

Results: Short Term Application of Magnets post QSRL Treatment

Immediate whitening of the area was seen upon treatment with QSRL (FIG.1B). However, in small areas of the tattoos, QSRL treatment caused localepidermal damage, e.g., epidermal erosions with a small amount of bloodor serous fluid appearing at the skin surface. External application ofmagnets for 1 hour following a QSRL treatment, did not significantlyaffect the brightness of tattoos (p=0.33) compared with laser alone. Atsites with epidermal damage, magnetite ink particles were extracted(removed) from the skin by magnet application. This was evident by theappearance of ink on the under surface of the tegaderm tape, whichoccurred only where the magnet was applied. Epidermal damage wasnecessary for ink to be extracted by magnets. Histologically, magnetapplication for 1 hour after QSRL caused a significant upward migrationof magnetite ink in the papillary dermis. Compared with control, therewas a predominance of ink particles in the papillary dermis (p<0.0001;FIG. 5) at or close to the dermo-epidermal junction in 11 out of 12samples (FIG. 3B). Coarse dermal spaces similar to those previouslydescribed after QSRL treatment of tattoos (Taylor et al., J. Invest.Dermatol., 97:131-136 (1991)), and a sparse dermal infiltrate were alsopresent. Areas with epidermal damage showed ink extending to the surfaceof the skin (FIG. 3C). A characteristic vertical streaking pattern ofthe ink particles was seen in the dermis only after magnet application,apparently along magnetic field lines. FIG. 3B shows a mature tattoo onehour after QSRL treatment followed by magnet application, showingincreased ink in the papillary dermis under an intact epidermis. FIG. 3Cshows a tattoo one hour post QSRL treatment followed by magnetapplication without an intact epidermis. The ink particles are streakedand extend to the tissue surface. This streaking pattern was not seen inthe tattoos treated with laser alone (p<0.0001; FIG. 6).

Results: QSRL Treatment Alone

One hour after QSRL treatment of tattoos, there was cellular debris butno magnetite particles on the under surface of the tegaderm tape.Biopsies revealed predominance of ink particles mostly in the reticulardermis with obvious focal disruptions of dermis and epidermis, and aninflammatory infiltrate (FIG. 4A). Laser treatment caused localdispersion of ink clusters compared with the untreated tattoos, butunlike sites after magnet application there was no streaking pattern orvertical alignment of the particles. Three weeks after QSRL treatmentalone, tattoos appeared lighter than the controls. However, bystatistical analysis of the pixel values the lightening was notsignificant (p=0.214). Complete healing of the treated area was seen,without any evidence of scarring, infection, granulation tissueformation or skin textural changes. Biopsies taken 3 weeks after QSRLtreatment, showed distribution of the ink particles throughout thereticular dermis similar to untreated tattoos. No streaking pattern wasseen (FIGS. 4B, 6).

Results: Long Term Application of Magnets Post QSRL Treatment

Application of magnets for 3 weeks after laser treatment, causedsignificant darkening of the tattoo under the magnet (p<0.0001),compared to tattoos treated with laser alone. No particles were detectedon the under surface of the magnet. Histological analysis showed inkpredominance in the papillary dermis and close to the dermo-epidermaljunction in 10 out of 12 samples, with some vertical streaking pattern(FIGS. 3D, 6). Consistent with the gross appearance of healing withoutscar, there was no residual inflammation or fibrosis.

Conclusions

Magnetic ink can be successfully used to make tissue markings, and thesetissue markings can be grossly and microscopically manipulated in vivoby external magnetic fields. Furthermore, the application of a QSRLtreatment followed by application of an external magnetic field produceda synergistic effect, resulting in even more efficient alteration of themagnetic ink tissue marking.

OTHER EMBODIMENTS

It is to be understood that while the invention has been described inconjunction with the detailed description thereof, the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Otheraspects, advantages, and modifications are within the scope of thefollowing claims.

1. A device for removing magnetic skin tattoos, the device comprisingmeans for producing a high product of the magnetic field strength andmagnetic field gradient within the skin, and a housing configured toenable the device to be contacted to the skin in the location of atattoo.
 2. The device of claim 1, wherein the means for producing a highproduct of the magnetic field strength and magnetic field gradientwithin the skin comprises at least one electromagnet.
 3. The device ofclaim 2, in which the electromagnet comprises a superconductingelectromagnet.
 4. The device of claim 2, in which the electromagnetcomprises a solenoid coil.
 5. The device of claim 1, wherein the meansfor producing a high product of the magnetic field strength and magneticfield gradient within the skin comprises at least one permanent magnet.6. The device of claim 1, wherein the device further comprises acontroller that varies the magnetic field spatially or temporally, orboth.
 7. The device of claim 1, further comprising a laser arranged toilluminate the location of the tattoo.
 8. The device of claim 7, whereinthe laser is a Q-switched ruby laser.